Dataset Information

Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine?

ABSTRACT: Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. KIT/PDGFRA-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of MGMT methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of MGMT methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.

SUBMITTER: Ravegnini G

PROVIDER: S-EPMC6463228 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine?

Ravegnini Gloria G Ricci Riccardo R

Epigenetics insights 20190412

Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. <i>KIT/PDGFRA</i>-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT) through promoter methyl ...[more]

PMID: 31020269

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Project description:Gastrointestinal stromal tumors (GISTs) that are not driven by kinase mutations, as are most GISTs, often show loss of function of the succinate dehydrogenase (SDH) complex and are considered SDH-deficient GISTs. SDH-deficient GISTs share many distinct characteristics compared with conventional GISTs. However, data regarding these characteristics, particularly among Asian people, are relatively limited. The objective of this study was to characterize the clinicopathologic characteristics, treatment, and prognosis of these uncommon GISTs.This retrospective observational study enrolled 12 patients with SDH-deficient GISTs, who were selected from 335 patients with GIST diagnosed at our institution between October 31, 2013 and October 31, 2016 by succinate dehydrogenase subunit B staining.There were 8 male and 4 female patients, with a median age of 57 years (range, 21-73 years). Ten patients (83.3%) were diagnosed at or after the age of 40 years and represented 7.2% (10/138) of the entire population of elderly patients with gastric GISTs. The tumor size ranged from 3 to 19 cm (median, 7 cm); the primary tumor was multifocal in 6 cases (50%), and tumors had a multinodular or plexiform architecture in 10 cases (83.3%). Ten cases (83.3%) showed pure epithelioid morphology, with the remaining 2 cases (16.7%) showing mixed histologic subtype. Lymph node metastasis was found at the time of primary resection in 50% (3/6) of patients. Four cases (33.3%) had distant metastasis at presentation. Four patients (33.3%) developed disease progression during imatinib treatment after initial resection, but all of these patients regained disease control when the treatment was altered to sunitinib targeted therapy.SDH-deficient GISTs arise exclusively in the stomach and account for approximately 7.4% (12/162) of gastric GISTs. Moreover, those affecting people older than 40 years are not uncommon and sunitinib may work well for cases showing treatment failure with imatinib.

Project description:A subset (7% to 10%) of gastric gastrointestinal stromal tumors (GISTs) is notable for the immunohistochemical loss of succinate dehydrogenase (SDH) subunit B (SDHB), which signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. These SDH-deficient GISTs are known to be KIT/PDGFRA wild type, and most patients affected by this subset of GISTs are young. Some of these patients have germline mutations of SDH subunit genes SDHB, SDHC, or SDHD, known as Carney-Stratakis syndrome when combined with paraganglioma. More recently, germline mutations in SDH subunit A gene (SDHA) have also been reported in few patients with KIT/PDGFRA wild-type GISTs. In this study we immunohistochemically examined 127 SDHB-negative and 556 SDHB-positive gastric GISTs and 261 SDHB-positive intestinal GISTs for SDHA expression using a mouse monoclonal antibody 2E3 (Abcam). Cases with available DNA were tested for SDHA, SDHB, SDHC, and SDHD gene mutations using a hybridization-based custom capture next-generation sequencing assay. A total of 36 SDHA-negative GISTs (28%) were found among 127 SDHB-negative gastric GISTs. No SDHB-positive GIST was SDHA negative. Among 7 SDHA-negative tumors analyzed, there were 7 SDHA mutants, most germline. A second hit indicating biallelic inactivation of SDHA was present in 6 of those cases. These patients had no other SDH subunit gene mutations. Among the 25 SDHA-positive, SDHB-negative GISTs analyzed, we identified 3 SDHA mutations (1 germline), and 11 SDHB, SDHC, or SDHD mutations (mostly germline), and 11 patients with no SDH mutations. Compared with patients with SDHA-positive GISTs, those with SDHA-negative GISTs had an older median age (34 vs. 21 y), lower female to male ratio (1.8 vs. 3.1) but similar mitotic counts and median tumor sizes, with a slow course of disease in most cases, despite a slightly higher rate of liver metastases. SDHA-negative GISTs comprise approximately 30% of SDHB-negative/SDH-deficient GISTs, and SDHA loss generally correlates with SDHA mutations.

Dataset Information

Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine?

Publications

Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine?

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